|Year : 2016 | Volume
| Issue : 2 | Page : 98-104
New psychoactive substances: Issues and challenges
Vaibhav Patil, Abhinav Tewari, Ravindra Rao
Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||4-Nov-2016|
National Drug Dependence Treatment Centre, Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
New psychoactive substances (NPS) have emerged as "legal" alternatives to internationally controlled drugs and commonly known by terms such as "designer drugs," "legal highs," or "herbal highs." These drugs are gaining popularity among youth in recent times as they are less expensive and easily available through head shops and internet. Till date, data about the extent and use of NPS in general population are limited. A large number of NPS are entering the user market due to the infinite possibility of altering the chemical structures of existing NPS to derive new substances, making them difficult to monitor. There is limited evidence of health damage associated with the use of NPS; research has also shown that some NPS have medical use also, which creates a dilemma for blanket control of all of these substances. Further, these drugs are not detected by traditional detection methods making them popular substitute for controlled substances, increasing challenges to laboratories and legal system. These issues and challenges would be important for clinicians, law enforcement authorities, and policy makers to consider for mounting an effective response to control the use of NPS.
Keywords: Designer drugs, herbal highs, legal highs, new psychoactive substances
|How to cite this article:|
Patil V, Tewari A, Rao R. New psychoactive substances: Issues and challenges. J Mental Health Hum Behav 2016;21:98-104
| Introduction|| |
The recent years have seen an increase in the sale and recreational use of new psychoactive substances (NPS). According to the United Nations Office on Drug and Crime (UNODC), NPS are substances of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but may pose a public health threat.  The term "new" does not necessarily refer to new inventions as several NPS were first synthesized even 40 years back, but "new" denotes those substances that have recently emerged in the drug market and which have not been scheduled under the international conventions. According to the UNODC report, the use of NPS has been reported in 95 countries and territories surveyed, making NPS a global problem.  NPS have emerged as "legal" alternatives to internationally controlled drugs and commonly known by terms such as "designer drugs," "legal highs," "herbal highs," or "bath salts." These drugs are less expensive and easily available as compared to the controlled substances. The possible number of such substances is unlimited due to the infinite possibility of altering the chemical structures of existing NPS to derive new substances.
NPS pose a number of issues and challenges which would be important for clinicians, law enforcement authorities, and policy makers to consider for mounting an effective response.
| Chemical Classes of New Psychoactive Substances|| |
[Table 1] provides classification of NPS. A brief description of the various NPS classes is as follows [Table 1].
Synthetic cannabinoids, which have similar effects as cannabis without the same threat of legal prosecution, are the most popular of NPS.  Initially, synthetic cannabinoids were developed and tested for their analgesic properties and to study neuronal receptors found in the body and brain.  Novel cannabinoids mimic the effects of cannabis as they activate primarily CB1 receptors. 
Synthetic cannabis users typically report subjective changes in sensation, altered mood states, cognitive impairments and disorganized thought, anxious and paranoid reactions, hallucinations, and dissociation. Other reported effects are nausea, palpitations, appetite stimulation, and "hangover-like" states, unlike prototypical cannabis effects. ,,
Aminoindanes (AIs) have effects on the release and uptake of serotonin, leading to their use as psychoactive substances. , They also have bronchodilating and analgesic properties.  The prototype AI, 2-AI, is a cyclic analog of amphetamine. Other members of this class include drugs such as 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodo-2-aminoindane, and N-ethyl-5-trifluoromethyl-2- aminoindane. Popular street names include "MDAI-gold" and "pink champagnes." There are no studies on the effects of these compounds on humans, but data from studies on rodents show that AI class of drugs produce neurotoxicity at high doses. 
Due to their structural similarity, ketamine and phencyclidine (PCP) are classified as arylcycloalkylamines, also called PCP-type substances. PCP was investigated as an intravenous anesthetic in 1950s but was later withdrawn due to undesirable effects such as dysphoria, confusion, psychosis, and delirium, following its use. Following that, ketamine was marketed as a medical alternative to PCP as anesthetic. Use of ketamine as a NPS was first reported in 1990s. Street names include special K, kit Kat, Vitamin K, and Cat-Valium. Ketamine is available in the form of liquids, powders, and capsules, and is usually inhaled or injected. Adverse effects include tachycardia, hypertension, pulmonary edema, and neurotoxicity. Chronic ketamine use has been shown to cause memory and cognitive dysfunction. 
Other PCP-type substances include 3-MeO-PCE and 4-MeO-PCP and are usually available in powder form. Acute adverse effects are reported ranging from mild neurologic abnormalities to stupor and coma. There are no studies showing the long-term effects of these substances on humans.
These are a diverse group of substances that include amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) (which are controlled under 1971 convention) as well as ring-substituted derivatives such as "2C series," "D series," benzodifurans (e.g., Bromo-Dragonfly), and para-methoxy-n-methyl-amphetamine. Their psychoactive effects have been reported to be dose dependent, with stimulant effect at lower doses and hallucinogenic and empathogenic effects at higher doses.  Street names include "Europa," "RDJ," 4-FMP, and methyl-MA. Phenethylamines are available as pills, powder, and liquid absorbed on blotting paper. These NPS are most commonly ingested. Adverse effects include vasoconstriction leading to tachycardia and severe limb ischemia, mydriasis, seizures, hallucinations, liver and renal failure, hyperthermia, and even death in some cases. 
Khat contains alkaloids such as katin, cathine, and cathinone and sold by street names such as "qat," "chat," "miraa," and "graba." Khat is usually consumed by chewing leaves. The acute effects of Khat resemble those of amphetamine use such as increased alertness, euphoria, hyperthermia, anorexia, increased respiration rate, heart rate, and blood pressure.  Prolonged use has been linked with psychosis, depression, organ damage, and neurological disorders. 
Kratom is derived from the tree "Mitragyna speciosa." It contains alkaloids such as mitragynine, mitraphylline, and 7-hydroxymitragynine, and has morphine-like pharmacological effects. Most commonly, it is available by the name "Krypton" which additionally contains caffeine and O-desmethyltramadol. Other street names of Kratom include "thang," "kakuam," "thom," and "ketum." Ingestion is the most common method of use. It acts as central nervous system stimulant at low doses, while at higher doses, it has sedative-narcotic effects. Fatalities have been reported to occur with its use. 
Salvia divinorum is a plant product containing neoclerodane diterpene (salvinorin A) as the active compound. It is usually sold as seeds or leaves, and consumed through chewing or making a drinkable infusion. Street names include "Diviner's Sage," "Salvia," "Sally-D," "Magic Mint," or "Purple Sticky." The acute effects of S. divinorum include hallucinations similar to that seen with Lysergic Acid Diethylamide (LSD) use. Animal studies have shown that consumption of S. divinorum is associated with minimal toxicity and addictive potential. 
The prototype for this group is cathinone, the principal active ingredient in the leaves of the khat plant (Catha edulis). Synthetic cathinones are usually sold in powder, pill, or capsule form disguised as "research chemicals," "plant food," "bath salts," or "glass cleaners." Ingestion is the most common mode of use, but these may be injected or inhaled. Typically, synthetic cathinones have an amphetamine-type analog. Cathinone, ephedrone, and methylone are structurally related to amphetamine, methamphetamine, and MDMA, respectively. The most common acute adverse effect is mild agitation; some users have severe psychosis. Other reported side effects include tachycardia, hypertension, and other sympathomimetic effects, and even death in some cases.
The prototype of this group is "tryptamine" which is a primary amine alkaloid. The effects of tryptamines are similar to natural hallucinogens. Tryptamine group of NPS includes substances such as 5-MeO-DPT, AMT, 4-AcO-DMT, 4-AcODiPT, and 5-HTP. Street names include "Foxy-Methoxy," "alpha-O," and "O-DMS." These are sold in capsule, tablet, powder, or liquid form. Tryptamines are generally swallowed, sniffed, smoked, or injected. Acute adverse effects include restlessness, agitations, gastrointestinal distress, and rhabdomyolysis.
Piperazines have been described as "failed pharmaceuticals" as many substances in this group were tested for their potential use, such as antidepressants, but never brought to the market. Examples include 1-benzylpiperazine, 1-(3-chlorophenyl) piperazine, 1-(3-trifluoromethylphenyl) piperazines, 1-benzyl-4-methylpiperazine, and 1-(4-fluorophenyl) piperazines. These are frequently sold as "ecstasy." Street names of piperazines include "pep pills," "social tonics," "Flying Angel," or "Legal X." These are most commonly available as pills and usually ingested. These have been found to have stimulant effects, but they can also lead to hallucinogenic effects. Acute adverse effects include seizures, respiratory acidosis, hyperthermia, rhabdomyolysis, and renal failure leading to fatality in some cases.
The above classification and type of NPS is not exhaustive, as newer NPS are constantly being synthesized, marketed, and used. Many NPS are popular at some point and then faded away. Consequently, NPS is associated with a number of issues and challenges. The issues and challenges are discussed under four headings: popularity and sale of NPS, health-related issues, challenges in laboratory detection of NPS, and legal challenges with NPS.
Popularity and sale of new psychoactive substances
Currently, systems related to collecting information on the sale and consumption of psychoactive substances which are internationally controlled have been established both nationally in many countries as well as globally. ,, As a result, countries have some understanding on the extent and pattern of the size of the internationally controlled substances' market in their jurisdiction. However, data about the extent and use of NPS in general population are lacking, and currently, limited data collected in few countries with respect to specific substances and subpopulations are available. The commonly used methodologies to study the extent of controlled psychoactive substance use cannot be applied to NPS, as transaction of NPS in terms of its sale and purchase or to its use does not follow the non-NPS substances.
Winstock and Baratt carried out an anonymous online survey on alcohol and drug use globally, and found that 17% among 14,996 participants had ever used synthetic cannabinoids.  Similarly, a study was carried out among nightclub-attending young individuals for which the participants underwent computer-assisted personal interview. Further, hair samples of those willing to provide were collected to be analyzed for the presence of selected synthetic cathinones ("bath salts") and some other NPS. The study found that about half of the hair samples (50%) contained MDMA, while 47.9% contained butylone and 10.4% contained methylone.  The Crime Survey for England and Wales used Computer-Assisted Self Interview to assess illicit drug use among adults aged 16-59 years.  The survey reported that 0.9% of the adult population used a NPS in the previous year of the survey. The use of NPS was concentrated among young adults - 4% of the adults aged 16-24 years had used a NPS in the last year, accounting for half of all NPS users. The chance of having used a NPS was higher among adults who had visited a nightclub or disco (3% compared to 0.5% among those who did not) in the last month. A telephonic survey conducted in 27 European Union member countries reported that 5% of young individuals aged 15-24 years used NPS.  Similarly, indirect data obtained through seizures of psychoactive substances and emergency visits by users also show increase in the use of NPS. For example, emergency department visits related to ecstasy use increased in the United States from 4,460 to 10,176 among those aged 21 years and below from 2005 to 2011. 
The use of NPS is increasing as an alternative to controlled substances such as morphine and ecstasy due to ease of availability. As they are not covered under the international conventions, manufactures have started selling them in the open market, reasoning that whatever is not expressly prohibited must be allowed for open sale. Access to these substances is easier as compared to illicit substances. These newer substances are sold mainly through "head shops" as research chemicals, food supplement, or as medicine. Head shops are also known as smart shops which are retail outlets specializing in the sale of NPS and/or drug paraphernalia. These shops are the major source of access to NPS that are not governed by regulatory laws. Usually, these drugs are sold in colorful packages which attract younger individuals. Sale through internet is also rapidly increasing in today's digital world. Youngsters have easy access to internet without the pressures of parental control or authority which makes them closure to the online NPS market.  Even new users can have all the information needed to purchase, sell, or use any NPS. As a result, there is a rapid increase in such online shops in the past 5 years. The EMCDDA reports that there were 651 online shops selling NPS in Europe in 2013.  NPS are available for sale on internet sites that are not easily accessible on search engines such as "Clearnet" and on the "Darkweb." Many of these sites do not require prescription for purchasing drugs. Online sale provides easy access to large numbers of consumers, reduces the operational costs, and allows anonymity for the producers as well as sellers.
Thus, the modality followed for the sale of psychoactive substances has changed with the advent of NPS. Internet and smart shops have emerged as the new places to sell NPS as compared to the street peddlers. Internet provides easy access to information and availability of NPS and makes it attractive for youngsters.
Health-related issues: Harmful or beneficial?
With the increase in the availability and use of NPS, reports of health hazards attributable to NPS have started emerging. Majority of NPS including mephedrone, MDPV, and synthetic cannabinoids have been developed in the past 10 years. Among these newer drugs, significant complications have been documented with mephedrone including seizures, severe agitation, myocarditis, and chest pain. , Harms associated with synthetic cannabinoid intoxication includes psychosis, panic/anxiety, and seizures. , In the recent years, numerous cases of acute intoxications and a few deaths associated with NPS intake have also been reported. , Fatalities have been reported with methylone and piperazine in many cases. ,, Some of the newer drugs such as GHB and Rohypnol are associated with criminal activities such as date-rape and robbery.  Many "legal highs" have also been found to contain controlled substances.
However, the harmful effects of NPS remain to be established unequivocally. Despite reports of mortality associated with NPS, data may be skewed due to comorbid use of other substances or to pre-existing morbid conditions, which may account for harmful effects associated with NPS.  For example, in a study on fatalities and criminal case, mephedrone was found to be the most common NPS; however, in 84% samples, alcohol and other drugs were also present, thus raising question on the role played by mephedrone alone in causing fatality.  At present, much of the data of death apparently related to NPS are available through case reports.  Most studies are based on work in animals, fatal poisonings in humans, or clinical observations in intoxicated patients. Scientific studies assessing toxicity, abuse liability, and risks associated with long-term use are lacking. Thus, the generalizability of the results is questionable.
Although majority of NPS have been associated with harmful effects, research has also shown the medical use of some NPS. For example, there have been various reports of ketamine showing rapid onset antidepressant effects in patients with treatment-resistant depression at subanesthetic doses. , Bupropion, a cathinone derivative, has been used as an antidepressant and as a stimulant in those with a history of cocaine misuse.  Currently, endocannabinoid system modulation has also been suggested as an approach for the treatment of a number of neurological illnesses (such as Parkinson's disease, Huntingdon's disease, or multiple sclerosis), cardiovascular illnesses as well as mood and anxiety disorders. 
Although there are encouraging reports on the possibility of the use of NPS for medical purpose, the harmful effects of NPS are highlighted on most instances. This creates a situation, whereby banning these substances is seen as the most effective way to curb their use. Curbing the use of these substances will also, unfortunately, close the possible doors for their legitimate medical use.
| Challenges in Laboratory Detection of New Psychoactive Substance|| |
Currently available urine or serum toxicology screens are unable to detect all newer drugs that have been synthesized. Standardized drug testing for NPS are not yet available in most laboratories. The increasing number of NPS also poses a challenge to traditional methods used to diagnose these substances. The heterogeneity in designer drug product contents, concentration, and chemical constituents have further increased challenges in detection.  Some NPS are designed by deliberately altering the psychoactive components of these drugs so as to circumvent legal controls. , Lack of detection on standard urine drug screening tests is a frequently reported reason for the use of the NPS. 
Metabolism of many NPS does not become known initially which results in delays in identification. Newly reported substances and their metabolites require properly certified reference materials to permit reliable identification and quantification. These reference materials are not available all the time. Commercial production of reference material of a given drug is a time-consuming process and usually takes 6 to 12 months to complete it. By the time the reference material becomes ready, a modified version of the same drug appears in market which is undetectable if the readied reference material is used. Research and development of reference materials also require a significant investment of capital and may not be seen as economically viable. Even if reference materials are available, use of primary analytical techniques such as nuclear magnetic resonance and high resolution mass spectrometry to identify novel material is not possible in routine laboratories.  However, early identification of drug is essential as establishing effective regulation becomes difficult once the market of a given drug crosses the tipping point.  The challenges to laboratories and legal system to detect newer psychoactive substances are less likely to abate in the near future.
| Legal Challenges Associated with New Psychoactive Substances|| |
NPS refers to those substances that are not subjected to control under international UN conventions. To be included in the list of controlled substances, a given drug must meet certain specific criteria. There should be clear evidence on the psychoactive property of the drug, extent or likelihood of producing abuse or dependence, likely impact on the public health and social problem, and its use in legitimate medical therapy. After this assessment by a group of experts constituted by the World Health Organization, further decision regarding its inclusion in the list of controlled substances is taken in the meeting of the Commission on Narcotic Drugs, through voting by the member countries. 
As little is known about NPS, it becomes difficult to arrive at a consensus on whether a particular NPS should be included in the list of controlled substances. As a result, NPS are not covered by laws or regulations that have global consensus and thus, fall out of global control system. This provides a large scope for the establishment of market for transnational drug trafficking. At present, the control of the supply of NPS is mainly dealt by national or regional responses which are still in infancy stage.  Countries are trying to control NPS mainly by using existing medicinal legislation or by extending and adapting the existing drug control legislations.
A major goal of the legislative ban on NPS is to curtail their sale and use, and this strategy also works to some extent. For example, when mephedrone, methylone, and MDPV were placed in Schedule I in the United States, reports from the poison control centers on their use have decreased.  Banning substances altogether may be intuitively effective, but has its unintended consequences too. For example, when synthetic cathinones were rendered illegal, biomedical research with these substances became difficult. This is despite the fact that the Food and Drug Administration has approved cathinone-related medications such as bupropion which is widely prescribed.  A common criticism on controlling the availability of NPS is also that these substances are placed in the most restrictive schedule, even though they pose minimal risk and/or might have potential benefits. The US congress, for example, placed GHB in Schedule I, even though GHB has shown potential for the treatment of narcolepsy as well as for alcohol and opiate withdrawal.  Though the legal acts have provision for the use of substances for research, restrictive scheduling may deter researchers for conducting research on these substances.  Banning of a particular NPS also results in the development of alternative substances; clandestine chemists have responded to drug scheduling of synthetic cathinones by synthesizing new "replacement" cathinones.  Thus, banning alone will not help in tackling the current situation with regard to NPS as it also prevents scientific research. Regional and international coordination is essential to handle legal challenges posed by these substances.
| Indian Scenario|| |
Indian data on the use of NPS and use-related health hazards are limited. Majority of information is available through newspapers; large-scale data on NPS are lacking. At present, the prevalence of NPS remains unknown. However, newspaper and anecdotal reports show increasing trends among young users. These substances have been reported to be used in rave parties, particularly in urban areas. , Indirect indicators of use such as seizure data have also raised concern over the growing use of NPS in India. As per data from the Narcotics Control Bureau, 1003 kg of mephedrone and 10 kg of ketamine were seized in-between January and March 2015.  India is also reported to be a major producer of NPS along with China.  Legal changes with regard to placing NPS under controls have not been carried out due to lack of sufficient data. At present, those found in rave parties are often booked under Section 27 of the Narcotic Drugs and Psychotropic Substances Act of 1985 and/or under Section 294 of the Indian Penal Code. , However, the government has recently placed ketamine under Schedule X of Drug and Cosmetics Act, 1940. Placing stricter controls over ketamine is also difficult, as ketamine remains the anesthetic of choice in rural areas for animals and humans alike. India needs to be concerned about the emergence of NPS due to its large population of young adults, easy access to internet, and lack of medical and legal preparedness to deal with NPS.
| Conclusion|| |
The problem of NPS is growing, both in terms of increasing number of substances available and increasing use. Data are insufficient to establish the extent of use of NPS among different populations. Studies on understanding the benefits and risks of NPS on public health are lacking. NPS will continue to be a challenge for public health and drug policy over the next few years. Special attention is required to be given to the speed at which NPS appear in the market and their open sale, especially in some countries. Strong national and regional early warning systems will play a central role in the early detection of NPS and ensure timely public health responses. Scientific research is essential to identify medical use of these substances; banning them will hamper future development of newer drugs. Considering changing trends of substance use, there is a need for raising awareness of them. Continuous monitoring will be needed for ensuring effective public health response.
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Conflicts of interest
There are no conflicts of interest.
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